In the field of anti-cancer chemotherapy it has been known for more than 25 years that solid tumors are amenable to treatment with antipyrimidine drugs i.e., pyrimidine inhibitors, such as 5-fluorouracil (5-FU or FU). (Darnowski et al, "Tissue-specific Enhancement of Uridine Utilization and 5-fluorouracil Therapy in Mice by Benzylacyclouridine" Cancer Research Vol 45, November 1985, pg. 5364). As discussed in The Pharmacological Basis of Therapeutics (Goodman & Gilman 5th Ed. 1975) pgs. 1272-1277 the therapeutic effect of 5-FU does not exist with the drug per se but in its enzymatically produced metabolite 5-fluoro-2'-deoxyuridine-5'-phosphate (F-dUMP) a nucleotide. This nucleotide has an unusually great affinity for the enzyme thymidylate synthetase resulting in a decreased DNA synthesis. A second mechanism of action of 5-FU may involve the incorporation of 5-fluoro-uridine-5'-triphosphate into RNA leading to impaired processing of nuclear RNA. (Groeningen et al, "Reversal of 5-fluorouracil Induced Myelosuppression by Prolonged Administration of High-Dose Uridine", Reports, Journal of the National Cancer Institute, Vol. 81, No. 2, Jan. 18, 1989, pg. 157). It has also been shown that 5-fluoro-2'-deoxyuridine-5'-triphosphate (FdUTP) is incorporated in DNA.
5-FU and other related antipyrimidine chemicals used alone or in combination with other anticancer agents are toxic to cancer cells and normal healthy cells. Accordingly, the dose of antipyrimidine compounds administered to patients undergoing cancer therapy is limited by the toxic effects exhibited by such compounds. It is also noted that the therapeutic index of such compounds, in general, is low. The low therapeutic index and the toxicity associated with such drugs has provided motivation for increasing the anti-tumor activity of the antipyrimidine drugs and decreasing toxic effects to host tissue. Positive results with 5-FU have been achieved by combining this antipyrimidine with other anti-cancer agents, such as methotrexate and N-(phosphonacetyl)-L-aspartate, PALA. It has also been demonstrated that healthy tissue, subjected to the toxic effects of certain antipyrimidine anti-cancer agents, can be selectively rescued by the subsequent administration of large doses of uridine which results in the elevation of plasma uridine concentrations in the plasma such that millimolar or high micromolar uridine levels can be measured in the plasma drawn from a patient (Darnowski et al Id.). The administration of uridine increases the pool of uridine available to both healthy and diseased cells and thus accelerates the clearance of the anti-cancer agent from these cells as the uridine competes with the anti-cancer agent. However, the normal cells are reported to clear the anti-tumor agent quicker than the cancer cells by selectively taking up uridine. Thus, uridine administration has been shown to provide rescue, resulting in an increased therapeutic effect, after the administration of antipyrimidine anti-cancer agents.
However, rescue with uridine is not without risk of debilitating side effects. It is reported that when uridine is taken intravenously patients experience fever and phlebitis (Martin et al, "Use of Oral Uridine as a Substitute for Parenteral Uridine Rescue of 5-fluorouracil Therapy, With and Without the Uridine Phosphorylase Inhibitor 5-benzylacyclouridine" Cancer Chemother Pharmacol, 24, 1989, pgs. 9-14). Phlebitis can be avoided. However, this requires administering uridine orally or through a central vein. Using the central vein as a route of administration is complicated and has inherent risks, but even central vein administration does not eliminate the incidence of fever. Intermittent administration of uridine is effective in preventing or lowering the incidence of fever but fever still develops in some patients, and all of these patients still suffer the risk and disadvantages of central vein administration.
To overcome these disadvantages it has been proposed to administer uridine orally. However, in order to rescue healthy cells and tissue, large doses of uridine are required. Uridine in large doses irritates the gastrointestinal tract, which frequently causes severe diarrhea. In cancer patients such a condition not only lowers the quality of the patient's life but subjects the less-than-healthy patient to the loss of fluids and electrolytes necessary for kidney maintenance. Of course, antipyrimidine chemotherapy may be only one of a number of treatments being simultaneously administered to the patient, and, therefore, any loss of fluid level caused by severe diarrhea may be fatal to the patient. Accordingly, the oral administered dose of uridine is limited by its toxicity and the limited dose may not provide successful rescue.
In order to be effective the administered uridine must be retained by the body long enough to allow for the incorporation of uridine into cells. However, at the liver level uridine is quickly catabolized and the breakdown compounds are easily excreted from the body. The use of 5-benzylacyclouridine (BAU), a phosphorylase inhibitor, in combination with uridine rescue is known to enhance the rescue effect by preventing the premature catabolism of uridine. The use of BAU prevents the breakdown of uridine by phosphorylase and the subsequent rapid body clearance of uridine, and thus slows the rate of uridine catabolism (Martin et al Id.). However, the administration of BAU fails to cure or eliminate all of the problems associated with administering i.v. uridine to patients.